Field of the Invention
This disclosure is related to the field of drug delivery via expandable catheters.
Description of the Related Art
Balloon angioplasty is an established method for the treatment of vascular disease by physically dilating an area of atherosclerosis, stenosis or reduction in luminal diameter in a diseased blood vessel. Angioplasty is typically performed with a catheter which may be advanced within the circulatory system to the diseased area. The catheter has a balloon at the distal end that is inflated to dilatate and expand the area of stenosis. In many cases, such as in the coronary arteries, a stent is also expanded on the exterior of the balloon. The stent is left in place after deflation and removal of the balloon to maintain the patency of the expanded lumen.
In order to achieve the physical enlargement of the vessel, large forces are exerted upon the tissues of the vessel during high pressure balloon inflation. The physical dilatation results in injury to the vessel, including endothelial disruption, fragmentation of the inner elastic lamina, and dissection of the vessel tunica media. Injury often extends into the outer adventitia as well. The biological response of the vessel progresses through a thrombotic phase during days 0 to 3, involving platelet activation and adhesion and thrombus formation. The thrombotic phase is followed by a cell recruitment phase during days 3 to 8 involving the infiltration of inflammatory cells, macrophages and lymphocytes, into the site of vessel damage. The release of growth factors and cytokines from the inflammatory cells lead to the proliferative phase during days 8 to day 14 in which the dormant smooth muscle cells in the tunica media of the vessel are stimulated to proliferate. Subsequently, the migration of the proliferating smooth muscle cells to the tunica intima and thrombus in the lumen results in neointimal hyperplasia, a primary component of restenosis. Although cell proliferation ceases after 14 days, continued production of extracellular matrix by the smooth muscle cells continues to increase the extent of neointimal hyperplasia and restenosis. The restenosis effectively reverses the dilatation treatment and potentially creates a critical threat to the patient. Human clinical studies have demonstrated that restenosis generally occurs 1 to 3 months after balloon angioplasty and the restenosis typically peaks at approximately 3 months.
Although balloon angioplasty provides a critical increase in blood flow in diseased vessels, restenosis is inherent due to the extent of associated mechanical injury. One strategy of reducing the restenosis response is to release drugs into the vessel in combination with the balloon dilatation treatment to counteract the inflammation and healing response. Approaches include the coating of the balloon with drugs, such as paclitaxel and sirolimus (rapamycin), which limit cellular proliferation. During contact of the balloon onto the luminal surface of the vessel it is believed that the coating facilitates transfer of the drug to the vessel injury site. These methods attempt to provide a drug concentration which is sufficient to reduce restenosis caused by cell proliferation and at the same time is low enough to minimize toxicity to the vessel that may result in damage or impairment of the vessel. It is believed that it is desirable to maintain an effective drug concentration for a sufficient time to minimize restenosis.
In practice, drug delivery to the tissues of the vessel wall by drug coated balloons as described in the art is limited by the short period of time during which the balloon may be placed in contact with the vessel. Typically the balloon inflation during angioplasty is performed for approximately 30 to approximately 120 seconds to limit cardiac ischemia and potential patient complications and discomfort. These short balloon inflation and drug delivery times may be sufficient for the antineoplastic drug paclitaxel which has demonstrated inhibition of neointimal formation in animals after a few minutes of exposure time. However, to provide maximum therapeutic effect and minimize potential high dose toxicity to the vessel, it would be desirable to provide delivery of drugs to the vessel over an extended period of time, ideally longer than the duration of balloon inflation. Additionally, drugs such as sirolimus and its analogues have both anti-proliferative and anti-inflammatory activity that may provide benefit beyond the acute period for restenosis if delivered over an extended time.
Many of the drug coated balloons described in the prior art use high initial levels of active agent and multiple treatments to create a high initial concentration, but then the concentration rapidly falls off. This is undesirable because most of the active agent on the device is lost as possible embolic particulate into the bloodstream, or by diffusion away from the treatment site.
Many of the drug coatings described in the prior art include hydrophilic polymers and excipients or excipients that are liquid at body temperature. Such hydrophilic coating formulations provide a hydrophilic matrix for the hydrophobic drug particles and may be effective at transferring the drug to the vessel wall. However, such coatings do not provide significant resistance to wash off from blood either during maneuvering of the balloon to the treatment site or after transfer of the drug coating to the vessel surface.